Dose-Response in Radionuclide Therapy Project Summary In this competing renewal application, our overall objective remains as previously described - to enable a patient- specific treatment planning approach to delivering radiopharmaceutical therapy (RPT) by establishing methodologies and developing computational tools that better predict tissue toxicity and tumor response. In the prior grant period we addressed RPT with beta-emitters and established a methodology to plan combination external beam radiotherapy with beta-emitter RPT. In this renewal application we propose to address the dosimetry of alpha-particle emitters. ?-particle emitters have been recognized as highly potent therapeutics that are fundamentally novel in their mechanism and largely impervious to resistance. The recent FDA approval of one such agent has led to numerous efforts to bring more alpha-emitter RPTs (?RPT) to the clinic. ?-particles are short-range (50 to 100 m,) high linear energy transfer (LET) particles which cause preponderant double- stranded break damage to DNA. Although there is a well-established dosimetry formalism for risk evaluation of these, there is no dosimetry formalism able to account for the high LET and the short range of these to evaluate toxicity and efficacy ? therapeutic endpoints. We propose to develop a methodology that accounts for the short range and high potency of these agents. The specific aims to do this are: 1. Measure the Relative Biological Effectiveness (RBE) of normal tissue for ?-particle emitter radiopharmaceuticals (?RPTs). No systematic evaluation of RBE for normal tissues has been undertaken. Currently available values are largely derived from in vitro cell studies. Since biological effect = Absorbed Dose (AD) x RBE, normal tissue RBE is needed to avoid toxicity, plan therapy, and safely execute phase I AD escalation trials for ?RPT.2. Measure tumor RBE, in vivo for 3 tumor types, compare to RBE, in vitro. Tumor RBE is needed to assess efficacy as well as for treatment optimization to avoid over-treating patients.3. Develop and incorporate macro to micro modeling for ?- particle emitter dosimetry into 3D-RD. The macro to micro approach developed with prior support has been implemented for kidney dosimetry of intact antibodies, labeled with different alpha-emitters. This aim will extend this work to peptides and small molecules and incorporate the method into the 3D-RD platform to establish a new version of 3D-RD (?3D-RD).4. Establish models that enable combined external beam RT (XRT) with ?RPT. There is a strong rationale for combining XRT with ?RPT. Such treatment has not been implemented because a methodology that incorporates micro-scale RBE-weighted dose distribution in dose maps and dose- volume histograms that can be used in XRT planning software does not exist. We will build upon the XRT-RPT method that we developed previously and that is currently being used with Sm-153, (a beta-particle emitter) in an ongoing clinical trial at Hopkins in patients with osteosarcoma to establish a formalism that can be incorporated into ?3D-RD. Successful completion of these aims will enable a dosimetry-driven, treatment planning approach to implementing this novel and highly potent therapeutic modality.